Substituted cinnamamides in myorelaxant compositions

ABSTRACT

THE PRESENT INVENTION CONCERNS NEW CINNAMAMIDES OF FORMULA:   (R1,R2,R3-PHENYL)-C(-R4)=C(-R5)-CO-N(-R6)-C(-R7)(-R8)-   CH(-R9)-R10   IN WHICH R1 AND R3 ARE HYDROGEN, A LOWER LAKYL OR LOWER ALKOXY RADICAL; R2 IS HYDROGEN, A HALOGEN, A LOWER ALKYL OR LOWER ALKOXY RADICAL; R4 AND R5 ARE HYDROGEN OR A LOWER ALKYL RADICAL; R6 IS HYDROGEN, A LOWER ALKYL OR LOWER HYDROXY ALKYL RADICAL ARYL RADICAL OR   C2H5NH-COO-C2H4-   R7 AND R8 ARE HYDROGEN, A LOWER ALKYL OR LOWER HYDROXY, ALKYL RADICAL; R9 IS HYDROGEN, A LOWER ALKYL OR LOWER HYDROXY ALKYL RADICAL; R10=HALOGEN, A HYDROXY RADICAL-EXCEPT WHEN R1 TO R9=H AND R1,R2,R3=CH3O,R4=CH3 AND R5 TO R9=H, A LOWER ALKYL RADICAL, A LOWER HYDROXYALKYL RADICAL, NH2-COO, A LOWER ALKYL RADICAL   -NH-COO   AND ARYL RADICAL-NH-COO. THE INVENTION IS REALTIVE TO PREPARATION PROCESSES AND MEDICINE CONTAINING AS ACITVE PRINCIPLE A CINNAMAMIDE OF FORMULA I, IN WHICH THE RADICALS R1 TO R9 HAVE THE SAME MEANINGS AS ABOVE AND R10=HALOGEN, A HYDROXY RADICAL EXCEPT WHEN R1, R2, R3=CH3O, R4=CH3 AND R5 TO R9=H-LOWER HYDROXY ALKYL, NH2COO, LOWER ALKYL   -NHCOO-ARYL-NHCOO

United States Patent "ice 3,659,014 SUBSTITUTED CINNAMAMIDES IN MYORELAXANT COMPOSITIONS Michel Bayssat, Louis Fontaine, and Marcel Grand, Lyon,

France, assignors to Lipha Lyonnaise Industrielle Pharmaceutique, Lyon, France No Drawing. Filed Mar. 31, 1970, Ser. No. 24,359 Claims priority, application France, Apr. 2, 1969, 6910054 Int. Cl. A61k 27/00 US. Cl. 424-324 Claims ABSTRACT OF THE DISCLOSURE The present invention concerns new cinnamamides of in which R and R are hydrogen, a lower alkyl or lower alkoxy radical; R is hydrogen, a halogen, a lower alkyl or lower alkoxy radical; R and R are hydrogen or a lower alkyl radical; R is hydrogen, a lower alkyl or lower hydroxy alkyl radical aryl radical or R and R are hydrogen, a lower alkyl or lower hydroxy, alkyl radical; R is hydrogen, a lower alkyl or lower hydroxy alkyl radical; R =halogen, a hydroxy radical-except when R to R =H and R R R =CH O, R =CH and R to R =H, a lower alkyl radical, a lower hydroxyalkyl radical, NH -COO, a lower alkyl radical and aryl radical NH-COO. The invention is relative to preparation processes and medicine containing as active principle a cinnamamide of Formula I, in which the radicals R to R have the same meanings as above and R =halogen, a hydroxy radical except when R R R =CH O, R =CH and R to R =H1ower hydroxy alkyl, NH COO, lower alkyl NHCOO-aryl-NHCOO The present invention relates to substituted cinnamamides.

Certain derivatives of cinnamamides are already known. The N-(Z-hydroxyethyl)-ci1mamamide has in particular been prepared by O. K. Behrens et al. J. Biol Chem. 175- 171-92 (1948). These authors studied this molecule solely as a biosynthesis intermediary, without investigating its pharmacological properties.

The present invention is particularly concerned, with novel substituted cinnamamides, as industrial products, and with new medicines containing substituted cinnamamides as active principles, which are outstanding as muscle relaxators, and in addition characterised by their low toxicity and their long duration of action.

The novel cinnamamides are represented by the formula in which R and R are each a member of the group consisting of hydrogen, a lower alkyl and lower alkoxy radical; R is a member of the group consisting of hydrogen, a halogen, a lower alkyl and lower alkoxy radical; R and R are each a member of the group consisting of hydrogen and a lower alkyl radical; R is a member of the group 3,659,014 Patented Apr. 25, 1972 consisting of hydrogen, a lower alkyl and lower hydroxyl alkyl radical, aryl radical and C H NHCOOCH R and R are each a member of the group consisting of hydrogen, a lower alkyl radical or lower hydroxyalkyl radical R is a member of the group consisting of hydrogen, a lower alkyl and lower hydroxyalkyl radical; R is a member of the group consisting of a halogen, a hydroxy radicalexccpt when R R R R R R R R and R are hydrogen-and when R R and R are a methoxy radical, R the methyl radical and R to R are hydrogena lower hydroxy alkyl radical, NH COO, loweralkyl NHCOO and aryl NHCOO.

The compounds of the invention, in the formulae of which R is a member of the group consisting of the hydroxy, lower alkyl and lower hydroxy alkyl radical, are obtained by condensation of a reactive derivative of a cinnamic acid capable of providing the group represented by Formula II, in which R R R R and R have the same meanings as previous: ly, with a hydroxy alkylamine of formula in which R R R and R have the same meanings as previously and R is a member of the group consisting of hydroxy radical and lower hydroxy alkyl radical.

The reactive derivative of the cinnamic acid is preferably an acid chloride, the acid anhydride or an ester.

The transformation of the cinnamic acids capable of permitting the introduction of the group of Formula II can be efiected by means of various reactants. To this end, it is possible to use phosphorous trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, sulphuryl chloride or thionyl chloride. However, it is preferred to use thionyl chloride for the preparation of the corresponding intermediate acid chlorides.

The reaction can take place at temperatures which are within the range from about 20 C. to about C. in the absence of a solvent or in a solvent which does not enter into reaction under the conditions being used. These solvents can, for example, be chloroform, methylene ch10 ride, ether, carbon tetrachloride, benzene and analogous solvents.

The acid halide which is obtained is then treated with the appropriate hydroxy alkylamine. This reaction can be effected at temperatures which are in the range from about 5 C. to about 50 C. As the reaction can be exothermic, it is preferred to effect this in a solvent which does not enter into reaction under the conditions being used. The solvents which can be employed are, for example, chloroform, dioxane, tetrahydrofuran and analogous solvents. It is possible to use an acid acceptor, such as sodium hydroxide, sodium carbonate, potassium carbonate, sodium' bicarbonate, potassium bicarbonate, pyridine, triethylamine and dimethylaniline. In certain cases, the hydroxyalkylamine can act as its own acid acceptor, by using an excess which is at least twofold of this latter.

The transformation of the cinnamic acids into corresponding acid anhydrides can easily be efiected by the interaction of a cinnamic acid with its corresponding acid halide. The resulting acid anhydride is then treated with an appropriate hydroxy alkylamine, thereby obtaining the desired amide.

The alkyl esters of cinnamic acids can easily be prepared by standard esterification processes. The amidation of intermediate esters can be effected by treatment with an appropriate hydroxy alkylamine under conditions which are well-known in the art.

The transformation of the alcohols according to Formula I into corresponding halides is easily eifected by means of difierent reactants, by reaction of the alcohol in question with a halogenated reactant. Thionyl chloride is the preferred reactant of the invention. The reaction can be .elfected at temperatures which are in the range from about 10 C. to about 50? C. in a solvent which does not enter into reaction under the conditions being used. Benzene is the preferred solvent of the invention. It is also possible to use an acid acceptor, such as pyridine. The transformation of thealcoholsaccordi ng to Formula I into carbamates is effected by means of an acylation agent of appropriate carbamic acid type. The expression acyl agent of carbamic acid type, as it is used here, designates one or more compounds capable of transforming a OH OH group into a group represented by the in which R and R are each a hydrogen atom or an alkyl or aryl radical, in one or more reaction steps. The

processes for transforming hydroxyl groups into carbamate groups are well-known in practice and it is possible to employ any process of this type which gives the desired carbamates of the invention.

A very convenient method of preparation consists in causing the alcohol of general Formula I (R =OH or a hydroxy alkyl'radical) to react with an agent of general formula:

a c x y (v) in which R is a halogen atom, an alkoxy radical or an aryloxy radical, and X is a halogen atom, and in causing the intermediary thus formed to react with ammonia or with an amine of general formula:

EN u

in which R and R have the same meanings as in the Formula IV.

Phosgene is preferably used in the first step and ammonia in the second step. The ammonia can be present, for example, in the form of ammonium hydroxide. The resulting carbamate can be obtained by conventional processes, such as extraction, concentration and crystallisation. As a modification, the alcohol of general Formula I (R =OH or a hydroxy alkyl radical) can be caused to react with an appropriate alkyl or aryl isocyanate.

Furthermore, the use of isocyanate gives carbamates in which R is a hydrogen atom and R is an alkyl or aryl radical. I --According to one of the objects of the invention, the new medicine described contains, as active principle, a hydroxy alkyl cinnamamide, represented by the Formula I, in which:

R and R are each a member of the group consisting of Thetherapeutic compositions containing, as active principle, a hydroxy alkyl cinnamamide as above are effective as myorelaxants at doses which are between and 1000 mg. per unit close, it being possible to regulate the posology to obtain the best possible therapeutic response.

Examples of preparations of compounds according to the present invention are given below, as well as pharmacological and clinical tests and examples of pharmaceutical formulations, which illustrate the invention in a non-limiting manner.

' EXAMPLE 1 N- (Z-hydroxyethyl cinnamamide, n m z M: 191.22

CH-COIIK-CH-CHOH- A solution of 968.4 g. (5.8 moles) of cinnamoyl chloride in 1000 ml. of dioxane is added dropwise to a solution of 835.2 g. (11.6 moles+20%) of ethanolamine in 800 ml. of dioxane. The temperature is kept in the region of 20 C. On completing the addition, stirring takes place for one hour at normal temperature, the solution then being poured into iced water+hydrochloric acid, where- I after the formed precipitate is suction-filtered, washed with water containing bicarbonate and then again with water. The product obtained after extraction with chloroform from the mother liquors is added to that obtained after drying.

The yield is of the order of to of a product which crystallises in ethyl acetate or acetone, in the form of beautiful white crystals. M.P.=100.5102.5 C.

Gravimetric analysis.Calculated (percent): C, 69.09; H, 6.85; N, 7.33. Found (percent): C, 69.33; H, 6.70=;'N, 7.53.

Infra-red spectrum (KBr): Cm.- nOI-INH 3.300 nCO 1.600 6CH'of CH=CH trans 975 S'adjacent Hs on the phenyl 715-770 EXAMPLE 2 N-(Z-chlorethyl) cinnamamide -CK CH CORE CH (EH 6).

7.2 g. (0.6 mole/10) of thionyl chloride are added dropwise, at a temperature below or equal to 45 C., to a solution of 11.4 g. (0.6 mole/ 10) of N-(Z-hydroxyethyD- cinnamamide and 4.8 g. (0.6 mole/10) of pyridine, in 40 ml. of benzene distilled over sodium. Boiling is maintained for 4 hours. The solution is taken up in water, extracted with benzene, dried over sodium sulphate and the solvent is driven ofi. The yield is of the order of 74% of product, which crystallises in a mixture (1:05) of hexane and dichlorethane Gravimetric analysis.-Calculated (percent): C, 62.99; H, 5.77; N, 6.68; Cl, 16.91. Found (percent): C, 63.05;- H, 5.79;N 6.53; Cl, 16.97.

in the form of beige-coloured flakes M.P.=103-104.5 C. (capillary tube).

Infra-red spectrum (KBr): Crnf NH 3.260 ,uCO 1.660 (SCH of CH CH trans 970 5 adjacent Hs on the phenyl 735-770 EXAMPLE 3 N-(Z-hydroxyethyl)para-chloro cinnamamide C H CINO -CH=CH-CQNH-CH2-CH20H Using the Working conditions of Example 1 and starting with 8 g. (0.4 mole/10) of parachl0ro cinnamic acid chloride a product is obtained which crystallises in the form of white needles in ethyl acetate and melts at 137- 138.5 C. in a capillary tube.

Gravimetric analysis.-Calculated (percent): C, 58.53; H, 5.36; N, 6.21; CI, 15.71. Found (percent): C, 58.72; H, 5.29; N, 6.06; Cl, 15.62.

Infra-red spectrum (KBr): Cm.- ,uOHNH 3.300 ,rCO 1.660 ECH of CH=CH trans 975 2 adjacent Hs on the phenyl 820 EXAMPLE 4 N-(2-chlorethyl)-para-chloro cinnamarnide C H Cl N M =244.12

-CE CH CONE -CH CH C1 Using the conditions of Example 2 and starting with 13 g. (0.575 mole/ 10) of N-(Z-hydroxyethyl)-para-chloro cinnamarnide, a product is obtained which crystallises in the form of yellow needles in dichlorethane and melts at 144146 C. in a capillary tube.

Gravz'metric anulysis.Calculated (percent): C, 54.11; H, 4.54; N, 5.74; Cl, 29.05. Found (percent): C, 54.15; H, 4.69; N, 5.80; CI, 28.93.

Infra-red spectrum (KBr): Cm. NH 3.280 ,rCO 1.660 (SCH of CH=CH trans 970 2 adjacent Hs on the phenyl 820 EXAMPLE N-(Z-hydroxyethyl)-para-methoxy cinnamamide C I-I NO M=2 21.25

-ca on com Qui 0x 01:

Using the conditions of Example 1 and starting with 16.3 g. (mole/ 12) of para-methoxy cinnamic acid chloride, a product is obtained which crystallises in ethyl acetate in the form of fine white flakes and melts at 122- 124 C. in a capillary tube.

Gravimetric analysis.-Calculated (percent): C, 65.14; H, 6.84; N, 6.33. Found (percent): C, 65.21; H, 6.65; N, 6.22.

Infra-red spectrum (KBr): Cm. ,uOH-NH 3.420-3300 ,uCO 1.650 6CH of CHQrans 975 2 adjacent Hs on the phenyl 8,20

6 EXAMPLE 6 N-(2-chloro)-para-methoxy cinnamamide C12H14C1NO2 -cn=cn-co m -cn -cH -c1 Using the working conditions of Example 2 and starting with 11.1 g. (0.5 mole/.10) of N(2-hydroxyethyl)- (para-methoxy cinnamamide, a product is obtained which crystallises in dichlorethane in the form of very small beige-coloured flakes and melts at 127128.5 C. in a capillary tube.

Gravimetric analysis.-Calculated (percent): C, 60.12; H, 5.89; N, 5.84; C1, 14.79. Found (percent): C, 60.30; H, 5.71; N, 5.76; C1, 1461.

Following the conditions of Example 1 and starting with 25.2 g. (0.15 mole) of cinnamoyl chloride, 13.5 g. (0.15 mole) of 2-rnethyl-2-amino-l-propanol and 12.6 g. (0.15 mole) of sodium bicarbonate, a product is obtained which crystallises in ethyl acetate in the form of fine white needles and melts at 132134 C. in a capillary tube.

Gravimetric analysis.-Calcu1ated (percent): C, 71.20; H, 7.82; N, 6.39. Found (percent): C, 71.35; H, 8.00; N, 6 .53.

Infra-red spectrum (KBr): Cm.- .:.OH-NH 3.290 ,uCO 1.660 (SCH of CH CH trans 9180 5 adjacent Hs on the phenyl 770715 EXAMPLE 8 N- (N-ethylethoxycarbamyl) -cinnamamide CHI-118N203 -cn=u corm-ca -cH -oco1m-c n 20 g. of ethylisocyanate are added to 3.8 g. (mole/50') of N-(Z-hydroxyethyl)-cinnamamide. Heating takes place and, at boiling point, the alcohol enters into solution and a White precipitate appears after refluxing for about 10 minutes. The ethyl acetate in excess is distilled. A product is obtained which crystallises as a white powder in dichlorethane. Yield of the order of M.'P.=148.5- 150.5 C. (capillary tube).

Gravimetric analysis.Calculated (percent): C, 64.10; H, 6.92; N, 10.68. Found (percent): C, 63.93; H, 7.02; N, 10.80.

Infra-red spectrum (KBr): Cm.- .NH 3320-3240 ,uCO l.6951.660 6CH of CH=trans 965 5 adjacent Hs on the phenyl 7180440 7 EXAMPLE 9 N- (N-phenylethoxycarbamyl) cinnamamide Following the operating conditions of Example 8, there are treated 1.9 g. (mole/ 100) of N-(Z-hydroxyethyD-cinnamamide and 1.4 g. (mole/100) of phenyl isocyanate, to which 15 ml. of carbon tetrachloride are added for homogenisation purposes, while being made tepid with agitation, and after standing, the precipitate is suctionfiltered. A product is obtained which crystallises in the form of white flakes in dichlorethane. Melting point: 152154 C. (capillary tube).

Gravimetric analysis.Calculated (percent): C, 69.66; H, 5.85; N, 9.03. Found (percent): C, 69.63; H, 5.86; N, 9.16.

al o

Following the conditions of Example 1 and starting with 4.8 g. (mole/50') of 3,4,5-trimethoxy cinnarnic acid tarnsformed into acid chloride, used in crude form, a product is obtained which crystallises in the form of fine white needles in dichlorethane and melts at 133134 C. in a capillary tube.

Gravimetric analysis.-Calculated (percent): C, 59.77; H, 6.80; N, 4.98. Found (percent): C, 59.82; H, 6.64; N, 5.08.

Infra-red spectrum (KBr): Cm.- ,uOH-NH 3.430-3320 [.LCO 1.650 6CH of CH=CH trans 9 65, 1 adjacent H on the phenyl 8-65 EXAMPLE 11 N-(N-ethoxycarbamyl)-cinnamamide C I-1 N M=234.25

Q-CH ca comics cs wors To 90 ml. (1.8 mole/) of a solution of phosgene in toluene are added 19.1 g. (mole/10) of N-(Z-hydroxyethyl)-cinnamamide in solution in 200 m1. of tetrahydrofuran and, at a temperature lower than or equal to 7 C., 23.4 g. (1.8 mole/10) of quinoline are added. A White precipitate appears. Ambient temperature is allowed to be reached, the quinoline hydrochloride in suction-filtered and dry ammonia gas is caused to bubble into the filtrate for 2 hours. The formed precipitate is suction-filtered, washed with Water and added to the organic filtrate which has been concentrated.

The yield is of the order of 60 to 70% of product, which crystallises in methanol in the form of colourless flakes. M.P.=170172 C. (capillary tube).

Gravimetric analysis.-Calcu1ated (percent): C, 61.52; H, 6.02; N, 11.96. Found (percent): C, 61.63; H, 6.15; N, 12.10.-

Infra-red spectrum (KBr): Cm. [.LNH 3.4103.315-3.28'5-3.210 C0 1.700-1680 BCH of CH=CH trans 9'70 5 adjacent Hs on the phenyl 725-765 EXAMPLE 12 N- 3 -hydroxypropyl) -cinnamamide C H NO M=205.25

@4211 c1: comr cs cs c5 01:

Using the working conditions of Example 1 and starting with 16.7 g. (mole/ 10) of cinnamoyl chloride and 30 g. (4 moles/10) of 3-amin0-1-propanol, a product is obtained which crystallises in the form of white scales in dichlorethane. M.P.= 82-84 C. (capillary tube).

Gravimetric analysis.-Calculated (percent): C, 70.21; H, 7.37; N, 6.83. Found (percent): C, 70.36; H, 7.48; N, 6.96.

Infra-red spectrum (KBr): Cm.- OI-L-NH 3.4-00-3.290 ,tco 1.650 50H of CH=CH trans 970 5 adjacent Hs on the phenyl 765-725 EXAMPLE 13 N- (Z-hydroxyl-propyl) -cinnamide C H NO M=205.25

-ca-=ca com; cs ron a Using the working conditions of Example 1 and starting with 13.4 g. (mole/ 12.5) of cinnamoyl chloride and 24 g. (4 moles/ 12.5) of l-amino-2-propano1, a product is obtained which crystallises in the form of a white powder in dichlorethane. M.P.=133-135 C. (capillary tube).

Gravimetric analysis.-Calculated (percent): C, 70.21; H, 7.37; N, 6.83. Found (percent): C, 70.40; H, 7.32; N, 6.87.

Infra-red spectrum (KBr): Cm.- ,uOH-NH 3370 3.300 CO 1.660 8CH of CH=CH trans 980 5 adjacent Hs on the phenyl 765-715 EXAMPLE 14 N-( 1,3-dihydroxy-2-methyl-2-propyl) -cinnamamide mHnN a Q-CH-OH-CONH-F E-CE OHI Following the working conditions of Example-1 and starting with 16.7 g. (mole/10) of cinnarnoyl chloride and 23 g.

2 moles 10 of 2-amino-2-methyl-propane-1,3-diol, a product is obtained which crystallises in the form of White. powder in dichlorethane. M.P. =-107 C. (capillary tube).

Gravimetric analysis.Calculated (percent): Q6636; H, 7.28; N, 5.96. Found (percent): C, 66.46; H, 7.44; N, 5.97. I I

Infra-red spectrum (KBr): Cm.- OH-NH 3.4203.310 ,uCO 1.660 6CH of CH=CH trans 975 adjacent Hs on the phenyl 772-710 EXAMPLE N-methyl-N-2-hydroxyethyl cinnamamide C12H15N02 CH=CH-COI|-ICHCHOH Following the conditions of Example 1 and starting with 16.7 g. (mole/10) of cinnamic acid chloride and 16.5 g.

2 moles of N-methyl-N-hydroxyethylamine, a product is obtained which crystallises in the form of a white powder in dichloroethane. M.-P.=7981 C. (capillary tube).

Gravimetric analysis.Calculated (percent): C, 70.21; H, 7.37; N, 6.83. Found (percent): C, 70.38; H, 7.58; N, 7.00.

Following the conditions of Example 1 and starting with 8.4 g. (mole/) of cinnamoyl chloride and 23 g.

mole 10%) of diethanolamine, a product is obtained which crystallises in dichlorethane'as a white powder. M.-P.=8082 C. (capillary tube).

Gravimetric analysis.Calculated (percent): C, 66.36; H, 7.28; N, 5.96. Found (percent): C, 66.56; H, 7.45; N, 6.08.

Infra-red spectrum (KBr): Cm." ,uOH 3.300 ,uCO 1.650 BCH of CH=CH trans 972 5 adjacent Hs on the phenyl 770-710 EXAMPLE 17 N-( l-hydroXy-Z-propyl -cinnamamide C12H15NO Following the conditions of Example 1 and starting with 8.4 g. (mole/ 20) of cinnamoyl chloride, 3.8 g. (mole/ 20) of alaninol and 4.2 g. (mole/20) of sodium bicarbonate, a product is obtained which crystallises as small white flakes in dichlorethane. M.P.=144146 C. (capillary tube).

Gravimetric analysis.Calculated (percent): C, 70.21; H, 7.37; N, 6.83. Found (percent): C, 70.29; H, 7.37; N, 6.92.

10 Infra-red spectrum (KBr): Cmf ,uOH-NH 3.300 ,uCO 1.660 5CH of CH=CH trans 985 5 adjacent RS on the phenyl 775-735 EXAMPLE 18 N-( 1.3-dihydroxy-2-propyl) -cinnan1amide C12H15NO3 --CH=CH-C0NH-0H-CH20H ca oa Following the conditions of Example 1 and starting with 6.5 g.

0.3 mole TM) or" cinnamoyl chloride, 2.7 g. (0.3 mole/ 10) of serinol and 3.8 g.

I 0.3 mole of sodium bicarbonate, a product is obtained which crystallises in the form of small white needles in dichlorethane. M.P.=12.6 C. (capillary tube).

Gravimetric analysis.-Calculated (percent): C, 65.13; H, 6.83; N, 6.33. Found (percent): C, 64.95; H, 6.66; N, 6.37.

EXAMPLE l9 N,N-bis-(2-hydroxyethyl)-paramethoxy cinnamamide C H NO M=265.30

CH 'CH OH ago Following the conditions of Example 1 and starting with 13.5 g. (0.75 mole/l0) of para-methoxy cinnamic acid chloride and 17.3 g.

mole

of diethanolamine, a product is obtained which crystallises as white needles in dichloroethane. M.P.'=95-96 C. (capillary tube).

Gravimetric analysis.Calculated (percent): C, 63.39; H, 7.22; N, 5.28. Found (percent): C, 63.19; H, 7.37; N, 5.15.

Infra-red spectrum (KBr): Cm.- ,uOH 3.320 ,uCO 1.650 (SCH of CH=CH trans 975 2 adjacent Hs on the phenyl 820 EXAMPLE 2-0 N,N-bis (Z-hydroxyethyl) para-chlorocinnamamide C13H1C1NO3 -cs=cB-co-it-cH -m 0r1 Following the conditions of Example 1 and starting with 14.6 g. (0.72 mole/ 10) of para-chloro cinnamic acid chloride and 33 g.

of diethanolamine, a product is obtained which crystallises as fine white needles in dichlorethane. M.P.=129 131 C. (capillary tube).

Gravimetric analysis.Calculated (percent); C, 57.89;

H, 5.98; N, 5.19; Cl, 13.15. Found (percent): C, 58.04; H, 5.91; N, 5.11; CI, 12.97.

Infra-red spectrum (KBr): Cm. OH 3.320 1.650 6CH of CH -CH trans 975 2 adjacent Hs on the phenyl 820 EXAMPLE 21 N-(2-hydroxyethyl)-3,4-dimethoxy cinnamamide C H NO M=251.28

ca a cu=(m-oomi-ca -ca oa CEO Following the conditions of Example 1 and starting with 22.6 g. (mole/ 10) of unpurified 3,4-dirnethoxy cinnamic acid chloride, a product is obtained which crystallises in the form of small white flakes in ethyl acetate. M.P.=122-123 C. (capillary tube).

Gravimetric analysis.-Calculated (percent): C, 62.13; H, 6.82; N, 5.57. Found (percent): C, 61.87; H, 7.05; N, 5.51.

Following the conditions of Example 8 and starting with 12 g. (mole/20) of N,N-bis-(2hydroxyethyl)cinnamamide and 20 g. of ethyl isocyanate, a product is obtained which crystallises in dichlorethane as acottony white product. M.P.=100-101 C. (capillary tube).

Gravimezric analysis.Calculated (percent): C, 60.47; H, 7.21; N, 11.14. Found (percent): C, 60.64; H, 7.43; N, 11.61.

Infra-red spectrum (KBr):

#NH 3.320 ,uCO 1.720-1.690-1.650 BCH of C-H=CH trans 975 adjacent Hs on the phenyl 767-710 EXAMPLE 23 N-[N-ethoxycarbamyl]-para-chloro-ci1mamamide H C H CIN O M= 268.70

-ca cs com! cs on occur:

Following the conditions of Example 11 and starting with 8 g. (0.35 mole/ of N-(2 -hydroxyethyl) parachloro cinnamamide,200 m1. of tetrahydrofuran, 35 ml. (0.7 mole/ 10) 01a solution of phosgene. in toluene and 11.5 g. (0.35 mole/4) of quinoline, a product is obtained which crystallises as small needles having a cottony appearance in methanol. M.P.= 195-196" C.

12 v 1 Gravimetric analysis-Calculated (percent): C, 53.63; H, 4.88; N, 10.43; Cl, 13.19. Found (percent): C, 53.77; H, 4.85; N, 10.31; Cl, 13.04.

r Infra-red spectrum (KBr): Cmf 0 NH 3430-3320-3210 .00 1700-1680 5CH of CH=CH trans 970 2 adjacent Hs on the phenyl 822 10 EXAMPLE 24 N- (2-hydroxy1-propyl) para-chloro-cinnamamide CmHmClNOg Following the working conditions of Example 1 and starting with 10.1 g. (mole/) of para-chloro-cinnamic acid chloride and 18.7 g. (mole/4) of 1-amino-2-propan01, a product is obtained which crystallises as small white needles in ethyl acetate and melts at -152 C. in a capillary tube.

Gravimetric analysis.-Calculated (percent): C, 60.12; H, 5.89; N, 5.84; Cl, 14.79. Found (percent): C, 60.30; H, 5.98; N, 5.67; Cl, 14.76.

Infra-red spectrum (KBr): Cm.- OH-NH 3.300 ,uCO 1.660 6CH of CH=CH trans 990 2 adjacent Hs on the phenyl 825 EXAMPLE 25 N- 1-bis-hydroxymethyl-Z-hydroxy) ethyljcinnarnamide C H N0 M=251.28

ca oa -CH=CH-GONH-C-BH2OH Following'the conditions of Example 1 and starting with 16.7 g. (mole/ 10) of cinnamoyl chloride, 30 ml. of dioxane, 26.6 g.

mole T of 2-amino-2-hydroxymethyl-propane-1,3-diol and 25 ml. of water, a product is obtained which crystallises as White needles of cottony appearance in ethyl acetate and melts at 152-154 C. in a capillary tube.

Gravimetric analysis.-Calculated (percent): C, 62.13; H, 6.82; N, 5.58. Found (percent): C, 62.25; H, 6.96; N, 5.55.

Infra-red spectrum (KBr):

uOH-NH 3.300 p.00 1.660 6CH of CH=CH trans 975 5 adjacent Hs on the phenyl 770-715 EXAMPLE 26 N-methyl-N-(2-hydroxyethyl)-parachloro-cinnamamide C H clNO M=239.70

-CH=CH-C0-N-CK2-CH2OK Following the conditions of Example 1 and starting with 10.1 g. (mole/ 20) of para-chloro-cinna'mic acid chloride and 15 g. (mole/5) of N-Z-methylamino ethanol, a

product is obtained which crystallises as white crystals in ethyl acetate. M.'P.=113115 C. in a capillary tube.

Gravimetric arzalysis.Calculated (percent): C, 60.12

H, 5.89; N, 5.84; CI, 14.79. Found (percent): C, 60.28;

Following the conditions of Example 1 and starting with 8.4 g. (mole/20) of cinnamoyl chloride and g.

mole +10%) of 3-amino-propane-1,2-diol, a product is obtained which crystallises as small white grains in dichloroethane and melts at 8587 C. in a capillary tube.

Gravz'm-etric analysis.Calculated (percent): C, 65.13; H, 6.83; N, 6.33. Found (percent): C, 65.06; H, 6.84; N, 6.24.

Infra-red spectrum (KBr): Cm. ,uOHNH (large) 3.300 ,nCO 1.665 6CH of CH=CH trans 970-980 5 adjacent Hs on the phenyl 755-700 EXAMPLE 28 N-phenylN-(Z-hydroxyethyl)-cinnamamide c qH qNofi Following the conditions of Example 1 and starting with 8.4 g. (mole/20) of cinnamoyl chloride and g.

of N-(2-hydroxyethyl)-aniline, a product is obtained which crystallises in a mixture of ethyl acetate and hexane (3:1) in the form of small white flakes and which melts at 73.5 to 745 C. in a capillary tube.

Gravimetric analysis.Calculated (percent): C, 76.38; H, 6.41; N, 5.24. Found (percent): C, 76.38; H, 6.48; N, 5.12.

Infra-red spectrum (KBr): Cm. ,uOH 3.440 [.LOO 1.650 fi CH of CH=CH trans 970 5 adjacent Hs on the phenyl 765708 14 EXAMPLE 29 N- 2-hydroxyethyl -a-methyl cinnamamide C12H15NO2 Q- on [a]- com! e11 0x 01! Following the conditions of Example 1 and starting with 15 g.

of ethanolamine in 15 m1. of dioxane and 9.05 g. (mole/ 20) of a-methyl cinnamic acid chloride in 25 m1. of dioxane, a product is obtained which crystallises as a cottony white product in ethyl acetate and melts at 1=07-,-109 C. in a capillary tube.

Grqvimerric analysis.Calculated (percent): C, 70.21; H, 7.37; N, 6.83. Found (percent): C, 70.38; H, 7.44; N, 6.90.

Infra-red spectrum (KBr) Cm.- ,uOHNH 3.300 ,uCO 1.650 5 adjacent Hs on the phenyl 750-705 EXAMPLE 30 N-(Z-hydroxyethyl)-fl-methyl cinnamamide 1 Following the conditions of Example 1 and starting with 3.6 g. (moles 2/100) of B-methyl cinnamic acid chloride (unpurified) and 10 g. of ethanolamine, a product is ob-. tained which crystallises in dichlorethane as White crystals and melts at -7'6.5 C. in a capillary tube.

Gravimetric analysis.-Calculated (percent): C, 70.21; H, 7.37; N, 6.83. Found (percent): C, 70.11; H, 7.37; N, 6.93.

Infra-red spectrum (KBr): Cur- ,uOHNH 3.270-3360 ,uCO 1.660 5 adjacent Hs on the phenyl 770-700 EXAMPLE 31 N-(Z-hydroxyethyl)-paramethyl cinnamamide Following the conditions of Example 1 and starting with 18 g. (mole/ 10) of para-methyl cinnamic acid chloride and 30 g. of ethanolamine, a product is obtained which crystallises in the form of beautiful colourless needles in ethyl acetate and which melts at 107108 C.

Gravimetric analysis.-Calculated (percent): C, 70.21; H, 7.37; N, 6.83. Found (percent): C, 70.33; H, 7.45; N, 6.92.

Following the'conditions of Example 1 and starting with 18 g. (mole/ 10) of .ortho-methyl cinnarnic acid chloride and 30 g. of ethanolamine, a product is obtained which crystallises in ethyl acetate in the form of white crystals and melts at 120-122 C. in a capillary tube. Gravimetrfc analysis-Calculated (percent): C, 70.2l; H, 7.37; N, 6.83. Found (percent): C, 70.06; H, 7.20; N, 6.86.

Infra-red spectrum (KBr): Cmr pOH--NH 3.320 .00 1.660 60H of CH=CH trans 980 4 adjacent Hs on the phenyl 765 EXAMPLE 33 N-(2-hydroxyethyl)-rneta-methyl cinnamamide C H NO M =205. 25

cx -H=0H-CONH-CK2-CH2OH Following the conditions of Example 1 and starting with 15.3 g. (0.85 mole/ 10) of meta-methyl cinnamic acid chloride and 26 g. (0.425 mole/ 10) of ethanolamine, a product is obtained which crystallises in dichlorethane as white crystals of monohydrate. M.P.=80-82 C. in a capillary tube.

Proportion of water. Calculated, 8.07% Found, 8.13% Gravimetric analysis.-Calcu1ated (percent): C, 64.54; H, 7.68; N, 6.27. Found (percent): C, 64.79; H, 7.63; N, 6.37.

Infra-red spectrum (KBr): Cm.- OH--NH 3.4503.260 ,uCO e 1.660 (SCH of CH=CH trans 970 3 adjacent Hs on the phenyl 780 PHARMACOLOGICAL TESTS (l) -I t Was possible to demonstrate the pharmacological activity'of this seriesof compounds on the muscular contractures. These compounds modify the polysynaptic reflexes, particularly at medullary level. The myorelaxation is investigated by evaluating the protective effect of the products against the mortal convulsions initiated by injecting strychnine subcutaneously into the mouse, the alkaloid modifying the chronaxis threshold of the association medullary neurons. 5 The product s'are administered by oral route, at of the LD to'the mouse, minutes'before the strychnine treatmenLIThe results are expressed as a percentage of protection of the animals against the mortal crises.

1a.. In the following Table I, the levels of protection ob served under the conditions as described are given as a percentage value of the standard compound ,(mephen; esin).

TABLET Survival test after strychnine sub- LD cutaneously, mouse treatment per perorally us at th Product in mg./kg. of LD Mephenesin 1. 400 Oinnamamide l. 400 18 Example:

(2) The complementary pharmacological investigation was continued in connection with the best compounds of the preceding series. The rats are decerebrated by section of the cerebral stem between the corpora quadrigemina. An electric nociceptive excitation of the plantar pulp initiates a contraction of the tibial muscle, which is recorded. The repeated excitations (every two minutes) are inhibited by administering myorelaxant substances by the digestive route (duodenal fistula). The values given in the following table represent the inhibition surface defined by the intensity 'of the inhibition and by the time which has elapsed between the disappearance of the response and the return of the contraction to t e original amplitude. The value 100 is attributed to the surface measured by the standard (dose given: DL mouse, per orally).

gain, if account is taken of the fact that the time for return to the normal response is 1 hour for mephenesin and 3 hours for the preferred compound.

1 .(3) Thorough investigation of the compound .of Example 1, designated as LCB 29 showed that:

(a) The duration of protection against the mortal crisis with strychnine'in the mouse is decidedly better than that observed with the best known products. When giving the compounds 10 minutes, 1 hour, 2 hours, 3 hours, 4 hours and 5 hours before injecting strychnine, it is constant that the protection of 50% of the animals of a batch (DP protective dose 50) is still seen, 5 hours after ingesting LCB '29, and only 2 hours after ingesting chlormezanone (the two products being given in an equitoxic dosez yi of the DL mouse per orally).

TABLE III Percentage of extension of the time for appearance of toxic signs in the treated mice, relatively to the control mice Time for Product at %th appearance of of the DL mouse, the first conperorally vulsive crisis Opisthotonos LCB 29 120 140 Chlormezanone. 35

(c) The central action of compound LCB 29 is not very pronounced. Its analgesic activity on the mouse, using the Sigmund technique, in an equitoxic dose, is /6 of the DL mouse per orally, which is equal to of that of aspirin.

(d) Similarly, the transquillising activity is weak. It is measured on the mouse by the funnel test of Boissier, Tardy and Diverres (Med. Exp. 19603-8l, 84). At 300 mg./kg. per orally, the preferred compound (LCB 29) only makes the test positive for 40% of the animals of the batch, whereas in an equitoxic dose A of the DL chlorodiazepoxide does this in 70% of the cases.

For the compound LCB 29, in the dose of 100 mg./kg. per orally in the mouse, the analgesic and tranquillising effects fall to zero values, whereas the myorelaxant activity is already very powerful.

(3) The cortical electrical activity, measured by electrocorticography on the rabbit in the coma vigil state, is not disturbed by doses reaching 5 mg./kg. administered intravenously, whereas in the same dose, mephenesin has a sedative effect shown by the synchronisation of the cortical branches and the desynchronisation of the deep layers (Rhynencepha-lon-Thalamus median),

(f) The toxic effects of compound LCB 29 are limited, as is apparent from the LD determined in connection with the mouse and the rat.

(g) The chronic intoxication of the rats absorbing compound LCB 29 in the ration up to the dose of 400 mg./kg. day for several weeks does not lead to any significant effect as regards behaviour, weight, and biological, hematological or histological effects.

(h) On the autonomous nervous system, the preferred compoundon a sleeping dog and in intravenous doses reaching 30 mg./kg.does not have any toxic effect. The arterial tension, choleresis, urinary flow, intestinal mortricity, renal vasomotricity, the central temperature, the respiratory rhythm and amplitude, the cardiac rhythm and the electrocardiogram in D2 are not significantly disturbed.

CLINICAL TESTS Clinically, the compound LCB 29, which is (N-(2- hydroxyethyl)cinnamamide, is found to be of very great interest in rheumatology, gynaecology, in functional rehabilitation and motive re-education, either after surgical operation, or long after paralytic attacks have abated, and also in neurological contractures-developed schlerosis in discs, paraplegia. Several clinical results are given here as examples to show the interest of the compound LCB 29,

considered as a medicine under such conditions. The

medicine is given per orally, in tablets each titrating 200 mg. of active principle.

Observation No. 1

Mr. Maurice Le G.: 46 years old.

Bilateral coxathrosis and lumbar arthrosis, without major antecedent.

Treatment: 3 tablets per day for 15 days.

The myorelaxant effect is investigated on the lumbar para-vertebral muscles (considerable contracture to the left due to lack of equilibrium of the pelvis) and on the adductor muscles of the coxas. There is a great improvement in the left para-vertebral contracture, which is apparent towards the tenth day of treatment. Distinct improvement in the intermalleolar distance. The subjective effect is very appreciable.

Observation No. 2

Miss Jeanne G.: 34 years old.

Post-traumatic after-effects at the level of the coxa, necessitating a functional re-education.

The treatment .with compound LCB 29 (3 tablets per day) makes it possible to obtain a very considerable muscular relaxation, with appreciable effect on the pains, The treatment is completed by application of a 10% ointment in the region of the coxofemoral joint. An intensive functional re-education is made possible.

Observation No. 3

Mr. Jean C.: 65 years old.

Schlerosis in discs developing for 10 years, with paralysis stage of the lower members with considerable stiffness. Numerous neurological signs, Babinsky positive.

The treatment lasts one month with 3 tablets per day.

The improvement is very considerable. The invalid, who was no longer able to ascend staircases, easily climbs several floors. He is able to Walk without the aid of a stick. Then bending of the leg at the thigh has become Very easy. The improvement continues.

Constantly, the treatment is very well tolerated.

FORMULATION The medicine containing the compound LCB 29 can be supplied in several suitable medicinal forms, such as tablets, injectable ampoules, suppositories and ointments for external use.

In the forms intended for internal use, the unit dose can vary from 10 to 1,000 mg. The daily dose can vary from 500 to 1,500 mg. Different formulations are given below, as non-limiting examples.

Tablet:

Active principle: 200 mg. Lactose: 50 mg. Royalgine: 10 mg. Starch: 10 mg. Talcum: 20 mg. Potato starch: 10 mg. Magnesium stearate: 4 mg. Injectable ampoule:

Active principle: 30 mg. ethanol: 5 mg. Distilled water: 5 ml.

In suppositories, the active doses as claimed are between 50 and 1,000 mg. As a non-limiting example:

Active principle: mg. Eutectic mixture of ester of fatty acids q.s.: 3 g.

For external use as an ointment, the active concentratrations can be from 1% to 20%. As an example and always in non-limiting manner:

Active principle: 10 g. Emulsified excipient of the oil-in-water-type, q.s.: 100 g.

., o I 19 What we claim is:' p 1. 'A'myorel'ax'ant composition in the form of a tablet, an injectable ampoule, a suppository and an ointment containing as its active principle a therapeutically effective amount of a cinnamamide of the formula:

in which R; and R are each selected from the group consisting of hydrogen, lower alkyl and lower alkoxy; R is' selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; R and R are each selected from the group consisting of hydrogen and lower alkyl; R; is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl and aryl; R

and R are each selected from the group consisting of hydrogen, lower alkyl and lower hydroxyalkyl; R is selected from the group consisting of hydrogen, lower except whenk R and R are methoxy, R is methyl, and R to R are hydrogen, in dosage form in a pharmaceutically acceptable carrier.

2. Myorelaxant composition according to claim 1 wherein the daily dose of active principle is between 500 and 1500 mg.

3. Myorelaxant composition in the form of a tablet, an injectable ampoule, a suppository, and an ointment containing as its active principle a therapeutically effective amount'of N-(Z-hydroxyethyl)-cinnamamide, in dosage form in a pharmaceutically acceptable carrier.

4. Myorelaxant composition according to claim 3 in which the dosage form is a suppository which contains between and 1,000 mg. of active principle.

5. Myorelaxant composition according to claim 3 in which the dosage form is an ointment in which the active concentration is from 1% to 20% .t

v References Cited Chem. Abst, 43-227 3e (227 1-2274 enclosed) (1949). V

STANLEY I. FRIEDMAN, Primary Examiner UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 659 03 Dated ggril 25, 1212 Invent Michel Bayssat et a1.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 2, "CI-IL?" should read ---'C2H}+-- Column 15, line 39, "C Hi No should read --C H NO Signed and sealed .this 29th day of August 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JH. ROBERT GOTISGHALK Attesting Officer Commissioner of Patents ORM PO-105O (10-69) USCOMM-DC 60376-P69 u.s. GOVERNMENT PRINTING OFFICE: I949 0-366-334 

